Process of manufacturing bis-4-hydroxy-coumarin esters



Patented Sept. 29, 1949 5.1 Y Z,

. 2,482,511? PROCESSOF MANUFACTURING BIS-4-" VHYDRQXY-COUMARIN ESTERS .J hBQ kiQ P a e; C s o ak a as Spojene farmaceuticke-zavody, .narodni podnik, Prague, Czechoslovakia No Drawing. Application February 14 1947, sei iigallsNo. 728,715. In Switzerland November 6,

; section 1 Public Law 690, August 8, 1946 v y Patent expires-November 6, 1965 .aolaims- (01. 260-3446) In my co-pending United States patent appliis conclusive of the fact that condensation has cation, Serial Number 728,714, filed on February taken place. 14, 1947, I have disclosed a process of manu- The reaction between two molecules of benzofacturing a derivative of the benzotetronic acid tetronic acid and one molecule of glyoxylic acid which reduces the prothrombin level of the blood. 5 ethyl ester ethyl alcoholate is as follows:

(IJH 0000221, on OH OH c /OH 0 000cm l eg -"6H2 g's'aiig aio Hz0 \1 o --I I A} =0 -c,H,oH o=o H 0= o r 0 o 0 For the manufacturing of this compound, the An interesting phenomenon was observed when ethyl ester of the glyoxylic acid is condensed with the melting point of the condensation product, benzotetronic acid or 4-hydroxy-coumarin. 3,3 carboxymethylenebis-(4-hydroxycoumarin) The compounds disclosed, such as 3,3'-carboxyethyl ester, was determined. The product as first methylenebis-(4-hydroxycoumarin) ethyl ester, obtained melts at 172 to 174 C. When the prodare characterized by their quick action on the uct is recrystallized from dilute acetic acid, this prothrombin level, which sets in already after melting point remains unchanged; if crystallized two to three hours after administration, and also, from methyl alcohol, the melting point decreases thereafter, by their quick elimination from the to 153 to 154 C.

organism. The physician by properly dosing these This product of lower melting point may be recompounds may thus keep the prothrombin 1eve1 converted by recrystallization into the product of of the blood elastically on the desired height, a 5 higher melting point.

fact which is of great importance for the practical The product acts as a weak acid and is soluble application of these compounds in therapeutics. in a bicarbonate solution and in alkalis, where- The object of this invention is a new and imfrom it may be reprecipitated by means of hyproved process for the manufacture of the 3,3 drochloric acid. carboxymethylenebis-(4-hydroxycoumarin) ethyl The effect of this product in animal tests has ester which enhance the smooth course of the been described in my aforesaid patent applicareaction and produce a higher yield by avoiding tion, Serial Number 728,714. As set forth therein, side reactions, particularly polymerization. when the product is administered per os to a I have discovered that this object is attained rabbit in a dose of 5 milligrams per kilogram of at, if in accordance with my invention, I employ weight of the rabbit, the decrease of the blood instead of glyoxylic acid ethyl ester, the glyoxylic prothrombin starts already within a short while acid ethyl ester ethyl alcoholate. and reaches the lowest level in the average within Since the alcoholate is an addition compound 18 hours, the titre moving between 20 to 30% of one alcohol molecule and one molecule of the of the normal value, determined by Quicks glyoxylic acid ester, the two components, during method. the condensation reaction, are readily separated Histological tests of organs did not show any from one another while the condensation takes changes, solely an accumulation of glycogen in place. The glyoxylic acid ester alcoholate thus the tissue of the liver. Particularly, after adminacts as a vehicle which facilitatesthe course of istration during an extended period of time, no the condensation and which while enhancing the damage to the capillaries was observed, in conlinking of the glyoxylic acid ethyl ester with trast with the administration of methylene-bisthe tetronic acid or bis-4-hydroxy coumarin, re- 4-oxycoumarin where such damages have been leases its alcohol molecule. observed.

The condensation may be carried out in the The following example will illustrate the presence of a solvent, at elevated temperature, manufacture of the compounds of the invention. such as water at boiling mp a acetone- It will be readily understood however that these The condensation product, produced by the reexamples are illustrative of the invention but action between benzotetronic acid and glyoxylic t 1 t t of it scope, acid ethyl ester ethyl alcoholate, will remain unchanged when heated with alcoholic potassium. Example When heated to 230 C., carbon dioxide will escape 7 gm. of benzotetronic acid are dissolved in and the residue will melt not below 300 C., which 750 cc. of water at boiling temperature and there- 3 after 10.5 gm. of glyoxylic acid ethyl ester ethyl alcoholate are added- After a. short while the liquid becomes turbid and gradually a White deposite is separated. The deposit is filtrated and dried in vacuo. The melting point. is 172 tic-174 C.; after recrystallization from methyl. alcohol eludes the step of reacting the reagents at elevated temperature, a

3. The process of manufacturing a 3,3-carboxymethylene bis-(l-hydroxycoumarin) ester which includes the steps of condensing benzotetronic acid with glyoxylic acid ethyl ester ethyl alcoholate, purifying the condensation product by dissolving it an alkali, precipitating it by means of an acid, and recrystallizing it.

JAN RosIcKY.

REFERENCES CITED The following references are of record in the file of this patent:

Sullivan et al.: Journal of the Amer. Chem. Society, vol. 65, Dec. 1943, pages 2288-2291. 

